1. Field of the Invention
The chemical compounds of the present invention belong to the class of antibacterial agents commonly called cephalosporins.
2. Description of the Prior Art
The preparation of pyridine derivatives (betaines or 3-pyridiniummethyl compounds) of cephalosporins began with such derivatives of cephalosporin C itself which were called the cephalosporin C.sub.A family. (See Biochemical J., 79, 403-408 (1961); U.S. Pat. Nos. 3,207,755; 3,219,662 and 3,226,384). Next came cephaloridine produced in that manner from cephalothin and also betaine derivatives of other 7-acylaminocephalosporanic acids; see Antimicrobial Agents and Chemotherapy, 573-580 (1967) in which the pyridine ring also contained substituents which were primarily alkyl or carboxamido groups but also included 3-COOH, 4-COOH (i.e., from nicotinic acids), 3-CH.sub.2 COOH and 3-SO.sub.3 H as well as halogens, nitriles etc. See also U.S. Pat. No. 3,449,338 in which claim 1 reads as follows:
"1. The compounds having the following formula: ##STR1## wherein R is a member of the group consisting of .alpha.-thienyl, .beta.-thienyl, .alpha.-furyl, and .beta.-furyl; n is 0 or 1; R.sup.1 is a member of the group consisting of hydrogen, methyl, ethyl, hydroxy, hydroxymethyl, trifluoromethyl, halo, cyano, carboxy, carbo(C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4) alkanoyl, (C.sub.1 -C.sub.4)alkanoyloxy, and ##STR2## attached to the pyridine ring in the 3 and 4 positions; R.sup.2 is a member of the group consisting of hydrogen, methyl, ethyl, and cyclopropyl; and R.sup.3 is a member of the group consisting of hydrogen, methyl, and ethyl."
See also U.S. Pat. Nos. 3,280,118 and 3,479,350 and U.K. Pat. No. 1,522,140.
Subsequent use primarily of pyridine and isonicotinamide is reflected in many patents in which there is generic disclosure having about the same breadth as that of U.S. Pat. No. 3,449,338 but containing no working examples or other details, as of preparation and properties, for any other compounds. Examples of early patents of this type are U.S. Pat. No. 3,217,000 (as well as U.S. Pat. Nos. 3,222,362; 3,222,363; 3,270,009 and 3,225,038) and 3,270,012 (see column 3).
Later such unsupported generalities appear, for example, in U.S. Pat. Nos. 3,483,197; 3,557,104; 3,632,810; 3,985,742 (see column 83); 4,024,134; 4,041,161 and 4,074,047. And see Derwent 23827A.
The hydroxylmethyl substituent is shown in U.S. Pat. No. 3,792,047. U.S. Pat. No. 3,790,565 reviews the literature.
In the 7-methoxy series of cephamycins see, for example, the listing in column 83 of U.S. Pat. No. 4,017,487 and column 3 of U.S. Pat. No. 3,775,410.
Sodium 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-phenylace tamido]-3-acetoxymethyl-3-cephem-4-carboxylate is described in Farmdoc (Derwent) abstract 65042X and see also Farmdoc 26113Y, 47004Y and 20763X and U.S. Pat. No. 4,061,748.
U.S. Pat. No. 3,945,995 describes the preparation of the N-hydroxysuccinimido ester of 4-hydroxy-1,5-naphthyridine-3-carboxyic acid.
As disclosed in our prior, copending U.S. application Ser. No. 874,456 filed Feb. 2, 1978 we have previously prepared the following compounds:
7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-phenylacet amido]-3-(4-carbamoylpyridinium)-methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(4-hydroxy phenyl)acetamido[-3-(4-carbamoyl-pyridinium)methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3,4-dihyd roxyphenyl)acetamido]-3-(4-carbamoylpyridinium)methyl-3-cephem-4-carboxylat e; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-chloro- 4-hydroxyphenyl)acetamido]-3-(4-carbamoylpyridinium)methyl-3-cephem-4-carbo xylate; PA1 7-[D-.alpha.(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-thienyl) acetamido]-3-(4-carbamoylpyridinium)-methyl-3-cephem-4-carboxylate. PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-phenylacet amido]-3-(4'-carboxypyridinium)-methyl-3-cephem-4-carboxylate; 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(4-hydrox yphenyl)acetamido]-3-(4'-carboxy-pyridinium)methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3,4-dihyd roxyphenyl)acetamido]-3-(4'-carboxypyridinium)methyl-3-cephem-4-carboxylate ; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-chloro- 4-hydroxyphenyl)acetamido]-3-(4'-carboxypyridinium)methyl-3-cephem-4-carbox ylate; PA1 7[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-thienyl) acetamido]-3-(4'-carboxypyridinium)-methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-phenylacet amido]-3-(3'-carboxymethylpyridinium)-methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(4-hydroxy phenyl)acetamido]-3-(3'-carboxymethylpyridinium)methyl-3-cephem-4-carboxyla te; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3,4-dihyd roxyphenyl)acetamido]-3-(3'-carboxymethylpyridinium)methyl-3-cephem-4-carbo xylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-chloro- 4-hydroxyphenyl)acetamido]-3-(3'-carboxymethylpyridinium)methyl-3-cephem-4- carboxylate; PA1 7[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-thienyl) acetamido]-3-(3'-carboxymethylpyridinium)methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-phenylacet amido]-3-(4'-carboxymethylpyridinium)-methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(4-hydroxy phenyl)acetamido]-3-(4'-carboxymethylpyridinium)methyl-3-cephem-4-carboxyla te; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3,4-dihyd roxyphenyl)acetamido]-3-(4'-carboxymethylpyridinium)methyl-3-cephem-4-carbo xylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-chloro- 4-hydroxyphenyl)acetamido]-3-(4'-carboxymethylpyridinium)methyl-3-cephem-4- carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-thienyl )acetamido]-3-(4'-carboxymethylpyridinium)methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-phenylacet amido]-3-(3'-sulfopyridinium)methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(4-hydroxy phenyl)acetamido]-3-(3'-sulfopyridinium)methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3,4-dihyd roxyphenyl)acetamido]-3-(3'-sulfopyridinium)methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-chloro- 4-hydroxyphenyl)acetamido]-3-(3'-sulfopyridinium)methyl-3-cephem-4-carboxyl ate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-thienyl )acetamido]-3-(3'-sulfopyridinium)-methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-phenylacet amido]-3-(3'-carboxypyridinium)-methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(4-hydroxy phenyl)acetamido]-3-(3'-carboxypyridinium)methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3,4-dihyd roxyphenyl)acetamido]-3-(3'-carboxypyridinium)methyl-3-cephem-4-carboxylate ; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-chloro- 4-hydroxyphenyl)acetamido]-3-(3'-carboxypyridinium)methyl-3-cephem-4-carbox ylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-thienyl )acetamido]-3-(3'-carboxypyridinium)-methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-phenylacet amido]-3-(2'-carboxypyridinium)methyl-3-cephem-4carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(4-hydroxy phenyl)acetamido]-3-(2'-carboxypyridinium)methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3,4-dihyd roxyphenyl)acetamido]-3-(2'-carboxypyridinium)methyl-3-cephem-4-carboxylate ; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-chloro- 4-hydroxyphenyl)acetamido]-3-(2'-carboxypyridinium)methyl-3-cephem-4-carbox ylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-thienyl )acetamido]-3-(2'-carboxypyridinium)-methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-phenylacet amido]-3-(4'-sulfoethylpyridinium)-methyl-3-cephem-4-carboxylate; PA1 7[-D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(4-hydroxy phenyl)acetamido]-3-(4'-sulfoethylpyridinium)methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3,4-dihyd roxyphenyl)acetamido]-3-(4'-sulfoethylpyridinium)methyl-3-cephem-4-carboxyl ate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-chloro- 4-hydroxyphenyl)acetamido]-3-(4'-sulfoethylpyridinium)methyl-3-cephem-4-car boxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-thienyl )acetamido]-3-(4'-sulfoethylpyridinium)-methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-phenylacet amido]-3-[3'-(2-carboxyvinyl)pyridinium]methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(4-hydroxy phenyl)acetamido]-3-[3'-(2-carboxyvinyl)pyridinium]methyl-3-cephem-4-carbox ylate; PA1 7[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3,4-dihydr oxyphenyl)acetamido]-3-[3'-(2-carboxyvinyl)pyridinium]methyl-3-cephem-4-car boxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-chloro- 4-hydroxyphenyl)acetamido]-3-[3'-(2-carboxyvinyl)pyridinium]methyl-3-cephem -4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-thienyl )acetamido]-3-[3'-(2-carboxyvinyl)-pyridinium]methyl-3-cephem-4-carboxylate ; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-phenylacet amido]-3-(4'-carboxymethylthiopyridinium)methyl-3-cephem-4-carboxylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(4-hydroxy phenyl)acetamido]-3-(4'-carboxymethylthiopyridinium)methyl-3-cephem-4-carbo xylate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3,4-dihyd roxyphenyl)acetamido]-3-(3'-sulfoethylpyridinium)methyl-3-cephem-4-carboxyl ate; PA1 7-[D-.alpha.-(4-hydroxy-1,5-naphthyridine-3-carboxamido)-.alpha.-(3-chloro- 4-hydroxyphenyl)acetamido]-3-(3'-sulfoethylpyridinium)methyl-3-cephem-4-car boxylate.
These compounds were found to be potent antibacterial agents but all of them had a solubility in water of less than 5 mgm./ml. This unfortunate characteristic renders them unsuitable for use by intravenous administration. Acceptable solubility for such use is at least 125 mgm./ml. so that 250 mgm. can be administered in 2 ml. of sterile solution. Suspensions cannot, of course, be administered intravenously. It was the object of the present invention to provide potent antibacterial agents, especially against Pseudomonas aeruginosa, having a solubility in water greater than 125 mgm./ml. and preferably of at least 250 mgm./ml. The latter would make possible a dosage of 500 mgm. in a 2 ml. vial.